Experimental induction of rhabdomyosarcoma in mice with fractionated doses of β-irradiation

Repeated doses of beta-radiation in the mouse skin model have been reported to produce carcinomas and sarcomas with equal frequency. Among sarcomas, fibrosarcomas and osteosarcomas have been the predominant reported histologies. In this report we describe the beta-radiation induction of rhabdomyosarcoma (RMS), a histology previously undescribed with tumor induction protocols using ionizing radiation in an animal model. Radiation-induced RMS is often seen as a secondary tumor following therapeutic irradiation for retinoblastoma in children. In our experiment the backs of 50 CD-1 mice were irradiated 3 times weekly for 35 weeks using a 90Sr source. The initial dose was 5.5 Gy/application, which was later reduced to 3 Gy after 15 weeks due to severe skin reactions. In all, 27 skin and subcutaneous tumors were seen and collected. Of 12 sarcomas seen, 9 had a rhabdoid histology; cell lines from 3 such tumors as well as a squamous-cell carcinoma (SCC) and a malignant fibrous histiocytoma (MFH) were established. Immunohistochemical analysis of their parent tumors showed that the rhabdoid tumors expressed desmin, which established the diagnosis of RMS. Two-dimensional gel electrophoresis and Western analysis of insoluble protein extracts confirmed that the cell lines from RMS tumors expressed desmin. A screen for molecular alterations identified a mutant p53 phenotype for RMS and MFH cell lines. These radiation-induced RMS cell lines provide a unique opportunity to study the molecular biology of this tumor in an animal model and will help provide insight into the mechanisms of radiation-induced RMS in humans.